Clinical and Experimental Otorhinolaryngology Vol. 10, No. 3: 228-235, September 2017
http://dx.doi.org/10.21053/ceo.2016.00612 pISSN 1976-8710 eISSN 2005-0720
Analysis of Prognostic Factors in Malignant External Otitis Sang Kuk Lee1·Se A Lee1·Sang Woo Seon1·Jae Hyun Jung1·Jong Dae Lee1·Jae Young Choi2·Bo Gyung Kim1 Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Bucheon;
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea
Objectives. Malignant external otitis (MEO) is a potentially fatal infection of the external auditory canal, temporal bone, and skull base. Despite treatment with modern antibiotics, MEO can lead to skull base osteomyelitis. Until now, there have been few studies on the prognostic factors of MEO. Methods. We performed a retrospective study to identify prognostic factors of MEO, and a meta-analysis of other articles investigating MEO. On the basis of disease progression the 28 patients in our study were divided into ‘controlled’ and ‘uncontrolled’ groups, consisting of 12 and 16 patients, respectively. We identified three categories of prognostic factors: those related to patient, disease, and treatment. We compared these prognostic factors between the controlled and uncontrolled groups. Results. In our study, the duration of diabetes mellitus (DM), presence of inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), and computed tomography or magnetic resonance imaging findings influenced the prognosis of MEO. In contrast, prognosis was unrelated to age, gender, mean glucose level, hemoglobin A1c level, pathogen, comorbidity, or cranial nerve involvement. No factor related to treatment modality was correlated with prognosis, such as surgery, steroid therapy, or interval to the first appropriate treatment. Cranial nerve involvement has been proven to be associated with disease progression, but the relationship between cranial nerve involvement and the prognosis of MEO remains controversial. As a part of this study, we conducted a meta-analysis of cranial nerve involvement as a prognostic factor of MEO. We found that cranial nerve involvement has a statistically significant influence on the prognosis of MEO. Conclusion. We found that glycemic control in diabetes mellitus, cranial nerve involvement, and the extent of disease determined from various imaging modalities influence the prognosis of MEO. We suggest that significant prognostic factors should be monitored to determine the prognosis of patients with MEO. Keywords. Otitis Externa; Malignant; Prognosis; Meta-Analysis
base. MEO tends to affect the elderly as well as patients with diabetes mellitus (DM) or other conditions resulting in immunodeficiency, such as human immunodeficiency virus (HIV) infection and chemotherapy. The most common causative organism is Pseudomonas aeruginosa (>90%) . Clinical manifestations include deep otalgia persisting for longer than 1 month, chronic otorrhea, headache, and cranial nerve involvement. Before the discovery of effective antibiotics, MEO had a mortality rate of up to 50%. Since the introduction of ciprofloxacin and other antipseudomonal agents in the 1990’s, the survival rate has improved . Nevertheless, MEO can be fatal if the disease continues to progress despite modern antibiotic treatment.
Malignant external otitis (MEO) is a potentially fatal infection of the external auditory canal (EAC), temporal bone, and skull ••Received May 5, 2016 Revised August 4, 2016 Accepted August 25, 2016 ••Corresponding author: Bo Gyung Kim Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, 170 Jomaru-ro, Wonmi-gu, Bucheon 14584, Korea Tel: +82-32-621-6951, Fax: +82-32-621-5018 E-mail: [email protected]
Copyright © 2017 by Korean Society of Otorhinolaryngology-Head and Neck Surgery. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lee SK et al. Prognostic Factors in Malignant External Otitis
MEO begins in the EAC, and then spreads to the skull base and the jugular bulb via the fissures of Santorini and the stylomastoid foramen. Venous channels and fascial planes facilitate the spread of infection along the dural sinuses, eventually resulting in extension to the petrous apex . Multiple studies have shown that cranial nerve involvement, primarily the facial nerve, is associated with advanced infection and progression of the disease. As the infection advances to the medial skull base, it reaches the jugular foramen, leading to involvement of the glossopharyngeal, vagus, and spinal accessory nerves . The hypoglossal nerve may be involved at its location within the hypoglossal canal, and with the progression of the infection, the nerves in the cavernous sinus could be affected as well. Severe complications, such as cranial nerve involvement and skull base osteomyelitis, are associated with increased risk of mortality. Many factors were believed to affect the prognosis of MEO, such as a medical history of DM, glucose level, cranial nerve involvement, and the extent of disease determined from various imaging modalities. However, further studies showed that these factors were not actually related to the outcome of MEO. For example, Mani et al.  reported that the presence of cranial nerve involvement did not affect patient survival rate under an optimized treatment plan. As reported by Soudry et al. , facial nerve involvement indicated progression of MEO, but did not, by itself, worsen prognosis. There is an ongoing debate regarding the various factors predicting the outcome for MEO. It is unclear which factor(s) lead to a poorer prognosis. Therefore, we analyzed prognostic factors in the hope of optimizing treatment strategy for this disease. We investigated the controversial prognostic factors and performed a meta-analysis of other articles investigating MEO retrospectively.
MATERIALS AND METHODS All cases of MEO diagnosed and treated by Department of Otolaryngology, Severance Hospital, Yonsei University Health System between January 2000 and March 2014 were identified. The diagnosis of MEO was based on the criteria set forth by Co-
H I G H L I G H T S The duration of diabetes mellitus, presence of inflammatory markers, and imaging findings influenced the prognosis of external otitis (MEO). None of the treatment-related factors, including surgery, steroid therapy, and the interval to the first appropriate treatment, were correlated with the prognosis. The meta-analysis of cranial nerve involvement as a prognostic factor showed that cranial nerve involvement had a statistically significant influence on the prognosis of MEO.
Table 1. The diagnostic criteria of malignant external otitis  Major (obligatory) signs 1) Pain 2) Exudate 3) Edema 4) Granulations 5) Microabscesses 6) Positive Technetium-99 (99Tc) scan of failure of local treatment after more than 1 week Minor (occasional) signs 7) Pseudomonas 8) Positive radiograph 9) Diabetes mellitus 10) Cranial nerve involvement 11) Debilitating conditions 12) Old age The diagnostic criteria of malignant external otitis (MEO) was divided into two categories: obligatory and occasional. All of the obligatory criteria must be present in order to establish the diagnosis. The presence of occasional criteria alone does not establish it.
hen and Friedman . We reviewed the records of 28 patients who met these criteria (Table 1). We examined the patients’ basic data, including interval to first intravenous antibiotic administration, presence of underlying disease, results of ear-nosethroat and neurologic examinations, results of imaging studies including computed tomography (CT) and magnetic resonance imaging (MRI), blood glucose measurements and level of glycemic control, treatment regimen, any surgeries performed, and the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. We divided the patients into two groups based on the outcome of treatment: controlled and uncontrolled groups. The controlled group included patients who recovered fully from MEO; the uncontrolled group included patients who did not recover or who died. All patients in the uncontrolled group were deceased at the time of the study. The clinical investigations were all conducted according to the principles expressed in the Declaration of Helsinki. This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University Health System (4-2016-0268). The two groups were compared using Student t-test, Fisher test, and the chi-squared test, as indicated; SAS ver. 9.2 (SAS Institute Inc., Cary, NC, USA) and Microsoft Office Excel 2003. A meta-analysis of other articles related to MEO was also performed. Several accepted sources were searched in order to identify primary studies published between 1974 and 2013. We primarily searched the Medline database, using the terms “malignant external otitis,” “malignant otitis externa,” “skull base osteomyelitis,” “necrotizing otitis externa,” and “infective external otitis.” Alternate spellings and an explicit search strategy were used for each source. All terms were searched in English. The literature search was extensive and was designed to obtain a large number of hits for MEO. In total, 368 articles were
Clinical and Experimental Otorhinolaryngology Vol. 10, No. 3: 228-235, September 2017
identified. After eliminating duplicates and articles on subjects obviously different from MEO, 342 publications remained for the period from January 1974 to April 2014 (Fig. 1). Most studies evaluating the prognosis for MEO were retrospective, so the meta-analysis was conducted on retrospective studies only. After eliminating articles with methodological restrictions and data limitations, six articles met our criteria for inclusion (retrospective study, complete reporting, and complete dichotomous outcome data). We used only the data on cranial or facial nerve involvement as a prognostic factor. We compared the outcomes for MEO using dichotomous data (controlled vs. uncontrolled group) from the retrospective studies. The data were analyzed using Stata ver. 8.2 (Stata Co., College Station, TX, USA). Our analysis was based on a random-effects model, which generates a wider 95% confidence interval (CI) for the pooled data. The relationship between cranial nerve involvement and the prognosis for MEO effect sizes were calculated as the natural log of the odds ratio (OR). Effect sizes are depicted with their respective 95% CI. 368 Initial search 26 Excluded - Obviously different subjects
342 Obviously different subjects 336 Excluded - Methodological restriction - Dara limitation 6 Include in study design
Fig. 1. Flow chart of search procedure. Table 2. Characteristics of the malignant external otitis patients Characteristic Gender Male Female Age (yr), mean±standard deviation Skull vase osteomyelitis Diabetes mellitus Comorbidity Cranial involvement First intravenous antibiotic administration (day) Steroid therapy Surgery
Controlled group (n=12)
Uncontrolled group (n=16)
9 3 62±16
13 3 68±9
3 7 4 6 29.0
16 16 12 7 32.6